Hypothalamic amenorrhea (HA), a reversible form of hypogonadotropic hypogonadism, has a population prevalence of <5% but is markedly increased in the setting of metabolic imbalance due to exercise and/or caloric restriction and stress. Interestingly, there is considerable inter-individual variability in the reproductive system response to apparently similar levels of diet, exercise and/or stress. We have now determined that women with HA have an increased burden of variants in genes association with Kallmann Syndrome or normosmic hypogonadotropic hypogonadism that may confer increased susceptibility to these physiologic stressors. We have also shown that the burden of variants in genes associated with the cross-talk between metabolic sensing and GnRH control through kisspeptin, GABAergic, glutaminergic, thyroid and orexin pathways is increased in HA vs control women. In normal women, moderate energy restriction for as little as 5 days is associated with sleep disruption for at least a full month augmenting the negative effect of the luteal phase on sleep. We have further shown that this degree of energy restriction results in adaptation of the thyroid axis as well as changes in appetite, leptin and orexin designed to conserve energy and increase appetite. Interestingly, the use of fatty acids as an energy source is not immediately reversed by consumption of a normocaloric snack. Finally, we have demonstrated that in women in whom LH pulse frequency is decreased in response to moderate energy restriction, individual responses to reduced energy availability prioritize either reproductive or metabolic adaptations.